Protein target for natural cancer treatment

Enzyme holds key to anti-cancer properties of bacterial product.

Many cancer sufferers turn to so-called natural products in a bid to fight the disease. Some of these products have a proven ability to help fight tumours, although the exact mechanisms are often unknown. Now US researchers have found a protein target for saframycinA (safA), a bacterial fermentation product which is active against various tumour cell lines.

SafA covalently modifies DNA and is structurally related to ecteinascidin (Et743), a marine-derived compound that PharmMar, a US firm, is putting through clinical trials to treat sarcomas of soft tissue and bone. Despite the growth in the number of small molecule anti-cancer compounds, it is not well understood how they actually inhibit cancer cell growth. Studies of Et743 have shown that the compound produces DNA-protein crosslinks but the identities of the proteins have eluded researchers. Now a team from Harvard University, Cambridge, MA, has found that an enzyme called glyceraldehyde-3-phosphate dehydrogenase (GADPH) is a protein target of DNA and SafA adducts. The enzyme is involved in processes such as DNA replication and repair and is overexpressed by many tumour cells.

The researchers found that SafA forms a complex with GAPDH and DNA. Furthermore, exposing cells to SafA increased the concentration of GAPDH in the nucleus, while cells with depleted GAPDH levels were resistant to SafA. Because healthy cells have lower GAPDH levels, the possibility springs to mind that a drug could be developed to target only cancer cells. Andrew Myers, who led the research team, won’t commit to this theory, but says that his team’s findings do ’suggest a potential basis for tumour cell specificity’. His research team still doesn’t know exactly why the ternary complex is toxic to cancer cells but is looking at many different things from the basic protein biochemistry to the identification of other proteins that may be involved.

Myers told Chemistry World that there has been commercial interest in his work but envisages that it will be a long time before drugs can be developed based on his team’s findings.

Emma Davies